The Markey Cancer Center (MCC), a dedicated matrix cancer center established as an integral part of the University of Kentucky (UK) and the UK Healthcare enterprise, has undergone dramatic expansion in recent years under the leadership of MCC Director Dr. B. Mark Evers. At this point in the center's development, the MCC seeks support through the National Cancer Institute (NCI) Cancer Center Support Grant to capitalize on this momentum and to drive a measurable reduction in cancer mortality in Kentucky, particularly Appalachian Kentucky, through a comprehensive program of cancer research, prevention, and patient care. The need for NCI Cancer Center designation is particularly acute in a state that leads the nation across numerous cancer indicators, including the highest rate of cancer deaths in the nation. Situated on a campus with all six health professions colleges in proximity to each other, the MCC offers a history of rich transdisciplinary collaboration, an outstanding program of cancer prevention and control that has produced seminal work in Appalachian Kentucky, nationally acclaimed basic research programs in cancer biology and DNA repair and oxidative stress, and a translational therapeutics program complemented by a top five College of Pharmacy. These strengths have coalesced in MCC's four thematic research programs: Cancer Cell Biology and Signaling; Cancer Prevention and Control; Drug Discovery, Delivery and Translational Therapeutics; and Redox Injury and Repair. Currently, the MCC's 108 Research and Associate Research members hold appointments in 24 departments in 7 colleges across the university (25 new faculty were recruited in the last 3 years). MCC members hold grants for 144 research projects funded in the annual composite (direct + indirect) amount of more than $30.5 million, of which over $11.3 million (37%) comes from the NCI. Accrual to therapeutic clinical trials has increased over 130% in three years, and MCC assignable space has increased 40%, including a doubling of state-of-the-art research space. In addition, six shared resources facilitate cutting-edge research by providing a robust infrastructure for specialized expertise and advanced methods. They include: Biospecimen and Tissue Procurement; Biostatistics; Cancer Research Informatics; Clinical Research and Data Management; Flow Cytometry and Cell Sorting; and Free Radical Biology in Cancer. The MCC is currently well positioned to take on new challenges and to continue to evolve in key strategic directions that take maximum advantage of these strengths.